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Review
. 2001 May;107(9):1063-9.
doi: 10.1172/JCI12881.

The Ehlers-Danlos syndrome: on beyond collagens

J R Mao  1 , J Bristow
Affiliations
Review

The Ehlers-Danlos syndrome: on beyond collagens

J R Mao et al. J Clin Invest. 2001 May.
No abstract available

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Figures

Figure 1
Figure 1
The biosynthetic pathway for the fibrillar collagens expressed in skin, identifying steps that are affected in different forms of EDS. (I) Collagen gene transcription is highly regulated, but haploinsufficiency for COL5A1 is uncompensated and leads to a reduction in COL5A1 mRNA and α1(V) procollagen chains. This accounts for 30–50% of classical EDS cases. (II) Many proline and lysine residues in the translated procollagen chains are hydroxylated by lysyl- and proline hydroxylases. Hydroxylation is essential for subsequent crosslinking and lysyl-hydroxylase deficiency causes the kyphoscoliosis form of EDS. (III) Procollagen α-chains are assembled into trimers within the rough endoplasmic reticulum (RER). Mutations in COL3A1 that interrupt the triple helical structure prevent normal processing and secretion of collagen III, causing the vascular form of EDS. (IV) In the ECM, the NH2- and COOH-terminal propeptides are cleaved by specific peptidases. Dominant mutations in COL1A1 and COL1A2 can prevent cleavage and cause arthrochalasia, while recessive loss of the N-procollagen peptidase cause dermatosparaxis. (V) Collagen molecules self-assemble into heterotypic fibrils. Dominant-negative mutations in COL5A1 and COL5A2 alter fibril assembly and cause some cases of classical EDS. (VI) Collagen fibrils are deposited in tissue-specific arrangements in close association with many fibril-associated proteins and proteoglycans. Because new fibrils are laid down in close association with the fibroblast cell membrane, interactions between the fibril and the cell are important and may involve direct interaction with collagens and/or matricellular proteins, including tenascin-X (TNX).
Figure 2
Figure 2
The collagen fibril and EDS. (a) Normal collagen fibrils are of uniform size and spacing. Fibrils from a patient with dermatosparaxis (b) show dramatic alterations in fibril morphology with severe effects on tensile strength of connective tissues. Most fibrils from a patient with classical EDS (c) are normal in appearance. Composite fibrils (arrows) are typically rare. Fibrils from a TNX-deficient patient (d) are uniform in size and no composite fibrils are seen. When compared with normal skin (e), TNX-null fibrils are less densely packed and not as well aligned to neighboring fibrils. In normal skin (e) and cornea (f), fibrils are deposited in tissue-specific patterns. In skin, bundles of fibrils are oriented in different directions to resist forces in multiple axes. In cornea, orthogonal arrays allow maximal transparency.
Figure 3
Figure 3
A novel deletion in the C4/CYP21/TNX/CREB-rp locus is associated with EDS. The C4 genes, the CYP21 genes and part of TNX are duplicated on chromosome 6. Dashed lines indicate the limits of the duplication event. The normal locus is shown in the top panel. Arrows indicate direction of transcription. TNX is overlapped at its 3′ end by the CYP21B (21B) gene encoding steroid 21-hydroxylase and, at its 5′ end, by CREB-related protein (CREB-rp). XA is a partial duplicate of TNX that is a pseudogene transcribed but not translated in the human adrenal. XA contains a 121 bp deletion (Δ) that truncates the open reading frame corresponding to TNX. CYP21A (21A) is a pseudogene. One-quarter of CYP21B-deficient alleles carry a 30 kb deletion extending from CYP21A to CYP21B (middle panel). This creates a nonfunctional CYP21AB fusion gene and deletes XA, but does not alter TNX. We described a similar deletion (lower panel) extending from XA to TNX that completely deletes CYP21B and creates a TNX/XA fusion gene. This deletion is associated with a new contiguous gene syndrome consisting of congenital adrenal hyperplasia, due to CYP21B deficiency, and EDS, due to TNX deficiency.
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References

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